Alpha-calcitonin gene-related peptide (αCGRP) and substance P (SP) are functionally correlated sensory neuropeptides deeply involved in bone homeostasis. However, they are usually studied individually rather than as an organic whole. To figure out whether they are interdependent, we firstly recorded the real-time αCGRP and SP levels in aging bone and healing fracture, which revealed a moderate to high level of αCGRP coupled with a low αCGRP/SP ratio in an anabolic state, and a high level of αCGRP coupled with a high αCGRP/SP ratio in a catabolic state, suggesting the importance of αCGRP/SP ratio in driving aging and healing scenarios. During facture healing, increase in αCGRP/SP ratio by adding αCGRP led to better callus formation and faster callus remodeling, while simultaneous addition of αCGRP and SP resulted in hypertrophic callus and delayed remodeling. The characteristics in inflammation and osteoclast activation further confirmed the importance of high αCGRP/SP ratio during catabolic bone remodeling. In vitro assays using different mixtures of αCGRP-SP proved that the osteogenic potential of the mixtures depended mostly on αCGRP, while their effects on osteoclasts and neutrophils relied on both peptides. These results demonstrated that αCGRP and SP were spatiotemporally interdependent. The αCGRP/SP ratio may be more important than the dose of a single neuropeptide in managing age-related and trauma-related bone diseases.

α-降钙素基因相关肽 (αCGRP) 和 P 物质 (SP) 是功能相关的感觉神经肽，与骨稳态密切相关。然而，它们通常是单独研究的，而不是作为一个有机整体进行研究。为了弄清楚它们是否相互依赖，我们首先记录了老化骨骼和愈合骨折中的实时 αCGRP 和 SP 水平，结果显示，在合成代谢状态下，αCGRP 水平中等至高，αCGRP/SP 比率较低，并且高水平的 αCGRP 与分解代谢状态下的高 αCGRP/SP 比率相结合，表明 αCGRP/SP 比率在驱动衰老和愈合情况中的重要性。在骨折愈合过程中，通过添加αCGRP增加αCGRP/SP比率导致更好的愈伤组织形成和更快的愈伤组织重塑，而同时添加αCGRP和SP导致肥厚的愈伤组织和延迟的重塑。炎症和破骨细胞激活的特征进一步证实了高αCGRP/SP比在分解代谢骨重塑过程中的重要性。使用不同αCGRP-SP混合物的体外测定证明，混合物的成骨潜力主要取决于αCGRP，而它们对破骨细胞和中性粒细胞的作用则依赖于这两种肽。这些结果表明αCGRP和SP在时空上相互依赖。在治疗与年龄相关和创伤相关的骨疾病方面，αCGRP/SP 比率可能比单一神经肽的剂量更重要。